The Power of Neuroactive Steroids
Click here to watch the companion YouTube video for this series.
In this series of three articles, I have sought to (1) provide an introductory guide to the power of neuroactive steroids, to (2) describe the dangers of the drug finasteride with particular respect to its effect on neuroactive steroids, and to (3) provide some preliminary ideas on how the reader may protect himself from these effects.
The first article in the series is the most difficult to get through. Expecting no background knowledge from readers, I have tried to provide as complete a picture of the biochemistry of neuroactive steroids as would be required to properly grasp the effect of finasteride. While difficult to get through, I encourage the reader to push through it, as the information is valuable for both the finasteride user and the modern biohacker.
While I have focused on 5a-reductase dependent sex and neurosteroids, I have also reviewed other steroids that have powerful neurological effects. I have only excluded two relevant steroids, testosterone and estrogen, because they are beyond the scope of this series. If you would like to learn about the cognitive and behavioral impacts of testosterone and estrogen, be sure to ask me about them on the next Instagram Q&A post.
With these disclaimers in place, let’s discuss neuroactive steroids.
STEROID BIOLOGY 101
Our bodies produce steroids from sterols, including cholesterol, in three separate places: the adrenals, the gonads, and the brain. Cholesterol is metabolized through a cascade of desmolases, hydroxylases, dehydrogenases, reductases, aromatase, and conjugation enzymes, into biologically active steroids. A neuroactive steroid is a steroid that affects neurotransmitter receptors in the brain, in addition to its effect on the testosterone, progesterone, and estrogen receptors in the brain. The effect on a neurotransmitter will produce a direct response from the brain, while the sex hormone receptor will produce a chronic effect, altering gene expression in the body. Classically, a neurosteroid is distinguished from a broadly neuroactive steroid by not having a communicative role at sex hormone receptors, though this turns out to be an oversimplification.
In this review, we will ignore the cognitive and behavioral effects of testosterone, dihydrotestosterone, and estrogens. We will be concerned with a precursor to testosterone in the hormone cascade, DHEA, as well as its sulfated form, and to the metabolites of testosterone, androstanediol and androsterone. We will also be concerned with the progenitor to all steroids, pregnenolone, and with the poorly understood neurosteroid THDOC. Finally, we will pay particularly close attention to the progestogens, which are progesterone and its metabolites allopregnanolone, and, to a lesser degree, isopregnanolone.
It is important to understand that all of the aforementioned steroids are in large part produced in the adrenals during stress. In that sense, they are part of the hypothalamic-pituitary-adrenal (HPA) adaptive stress response of the human. For this reason, interfering with their production can be thought of as changing our bodies’ stress response. Nonetheless, with the exception of THDOC, they are also produced directly in the brain.
THE METABOLISM OF NEUROSTEROIDS
Through intermediates, progesterone is synthesized from cholesterol during the luteal phase of a woman’s menstrual cycle, in the ovaries. During pregnancy, it is synthesized mainly by the placenta. During periods of stress, it is synthesized by the adrenal glands under the control of adrenocorticotropic hormone. While in women, systemic progesterone is derived both of the ovaries and the adrenals, in men systemic progesterone originates entirely from the adrenals.
Though progesterone freely crosses the blood-brain barrier, progesterone is also a neurosteroid, synthesized in the brain both by neurons and glial cells. Cholesterol is also neurosteroid. 25% of the body’s cholesterol is in the brain, and it is synthesized locally in the brain by glial cells, as cholesterol cannot bypass the blood-brain or blood-nerve barriers.
To synthesize neurosteroids in the brain, cholesterol must be transported across the mitochondrial membrane. This occurs through a molecular complex formed by 4 members: the translocator protein 18 kDa (TSPO), the steroidogenic acute regulatory protein (StAR), the voltage-dependent anion channel protein (VDAC), and the adenine nucleotide transporter protein (ANT). The rate-limiting step is TSPO. Once in the mitochondria, cholesterol is converted into pregnenolone by the P450 side-chain cleavage enzyme (p450scc). After cholesterol is converted into pregnenolone, the enzyme 3b-hydroxysteroid dehydrogenase (3BHSD) produces progesterone in the cytoplasm or mitochondria. Progesterone is then metabolized by the type 1 5a-reductase enzyme, that finasteride targets, into dihydroprogesterone (DHP). DHP is then metabolized by the 3a-hydroxysteroid oxidoreductase (3AHSOR) into allopregnanolone or by 3b-hydroxysteroid oxidoreductase (3BHSOR) into isopregnanolone.
Because the activity of 3AHSOR is greater than 5AR, 5AR is the rate-limiting step in the synthesis of neurosteroids in the brain. Also, note that there are three isoforms of the 5a-reductase enzyme (5ARs). Type 1 5ARs are abundantly expressed in the hypothalamus, hippocampus, cerebellum, and cerebral cortex. The type 2 isoform is almost undetectable in the adult human brain, though it is widespread in the body. Finasteride and dutasteride both inhibit the type 2 and type 3 isoforms. Finasteride partially inhibits the type 1 isoform, while dutasteride inhibits it fully. This means that finasteride will reduce DHP, allopregnanolone, and isopregnanolone, while dutasteride will almost entirely prevent their synthesis.
From pregnenolone’s other metabolite 11-deoxycorticosterone (DOC), dihydrodeoxycorticosterone (DHDOC) is produced through the 5AR enzymes. DHDOC is then metabolized by the 3a-hydroxysteroid dehydrogenase (3BHSD) enzyme into the neurosteroid tetrahydrodeoxycorticosterone (THDOC). Unlike allopregnanolone, THDOC is not present in the brain after adrenalectomy and gonadectomy, and thus appears not to be synthesized in the brain. It is produced following acute stress and peaks 10-30 minutes after the stressor. As THDOC is highly lipophilic, like the other neurosteroids, it readily passes the blood-brain barrier.
While progesterone and DOC are made directly from pregnenolone, testosterone is produced indirectly through the cascade, from either dehydroepiandrosterone (DHEA) through the same 3BHSD enzyme that converted pregnenolone into progesterone, or from androstenedione. In the brain, testosterone is then converted into dihydrotestosterone (DHT) by the type 1 5AR, and DHT is further converted into 3a-androstanediol (androstanediol) through the same 3AHSOR enzyme that converted DHP into allopregnanolone. Androstanediol is then converted by the 17b-hydroxysteroid dehydrogenase enzyme into androstenedione. (Note that androstanediol’s 3b-androstanediol isomer is not a neurosteroid – in this series, androstanediol refers to the 3a isomer only).
Having briefly reviewed the metabolisms of the neuroactive steroids pregnenolone, DHEA, allopregnanolone, isopregnanolone, THDOC, androstanediol, we shall next characterize their effects in the brain. Note that pregnenolone and DHEA are both actively converted into sulfated forms by the enzyme steroid sulfatase, and that the sulfated forms have different effects on cognition and behavior.
NEUROSTEROIDS AND GABAA
Recall that neurosteroids have an acute effect on brain neurotransmitter receptors and a chronic effect on gene transcription through their weaker effect at the sex hormone receptors of androgen, progesterone, and estrogen. The focus of much of the direct effect of neurosteroids is the inhibitory GABAA receptor. While allopregnanolone, THDOC, androstanediol, and androsterone potentiate or allosterically modulate the GABAA receptor, pregnenolone sulfate and DHEA sulfate produce a biphasic action at the GABAA receptor and enhance the excitatory glutamatergic NMDA receptor function. Another progesterone metabolite, isopregnanolone, also acts antagonistically at the GABAA receptor. Broadly, allopregnanolone, THDOC, androstanediol, and androstenedione are inhibitory neurosteroids while pregnanolone sulfate, DHEA sulfate, and isopregnanolone are excitatory. Note that androstanediol and androsterone potentiate GABAA with less potency than allopregnanolone and THDOC. Consequently, allopregnanolone and THDOC are considered the most powerful neurosteroids.
When the GABAA receptor is in the presence of the neurosteroids allopregnanolone, THDOC, androstanediol and androstenedione, there is an enhanced probability of the receptor chloride channel being open, such that the average time of the channel being open increases and the closed time decreases, resulting in an inhibition of neuronal excitation. Unlike benzodiazepines, which agonize only GABAA receptors that contains g2 subunits and do not contains a2 or a6 subunits, neurosteroids modulate most GABAA receptors, including recombinant versions. GABAA receptors that contain a d subunit are the most sensitive to neurosteroids, and transgenic mice lacking the d subunit show reduced sensitivity to neurosteroids. Interestingly, GABAA receptors that contain the d subunit have less potential to be desensitized and are usually located extrasynaptically.
Though neurosteroids allosterically modulate the GABAA receptors, at pharmacologic concentrations north of 10 micromolar, they can directly agonize the receptors, even in the absence of the neurotransmitter GABA. In this action, neurosteroids resemble barbiturates but not benzodiazepines.
The sulfated versions of pregnenolone and DHEA, which are found abundantly in the brain, reduce the frequency at which the GABAA channel open when found at physiologic doses. At the nanomolar or high micromolar concentrations of pharmacologic doses, they become potent allosteric agonists, increasing the frequency of the channel opening and the total duration of channel opening. Nonetheless, in normal physiology, allopregnanolone, THDOC, androstanediol, and androstenedione positively modulate the receptor, while pregnenolone sulfate and DHEA sulfate (as well as isopregnanolone) negatively modulate the receptor.
OTHER NEUROTRANSMITTER RECEPTORS
Although research on the molecular mechanisms of neurosteroids is still in its infancy, we do know that they affect more than the GABAA and NMDA receptors. Pregnenolone, pregnenolone sulfate, DHEA sulfate interact with the little understood s1 receptors. It appears that the sulfate versions act as agonists and pregnenolone acts as an antagonist, though the mechanisms are not understood.
Allopregnanolone also modulates serotonin type 3 receptors and nicotinic cholinergic receptors at micromolar potencies, and agonizes the pregnane xenobiotic receptor. There is also some evidence that either allopregnanolone or THDOC allosterically modulate dopaminergic receptors. THDOC also affects cholinergic receptors, as it has been shown to regulate the enzyme acetylcholinesterase, which degrades acetylcholine in the brain. Finally, although neurosteroids were once thought to be entirely inactive at sex hormone receptors, allopregnanolone has been shown to bind with progesterone receptors with nearly 8% the affinity of progesterone.
THE REMYELINATION OF AXONS
Lipid-rich, insulating myelin sheaths surround axons in the nervous system, and their integrity affects the conduction of nerve impulses and supports the survival of neurons. 25% of myelin lipids are composed of cholesterol. Myelin disorders, like multiple sclerosis, are characterized by axonal degeneration and neuronal death. People with multiple sclerosis exhibit decreased 5AR expression and allopregnanolone in cerebral white matter. In the peripheral nervous system, progesterone is synthesized by the myelinating Schwann cells. In the central nervous system (CNS), progesterone is produced by glial cells and adding progesterone to glial cells increases the proportion of oligodendrocytes, which are the myelinating cells of the CNS. Oligodendrocytes actively metabolize progesterone, either from circulation or from glial cells, into DHP, which plays a role in myelination.
Administration of progesterone to middle-aged male rodents doubled remyelination rates. It appears that progesterone and its derivatives’ (henceforth, the progestogens) effect on myelination depends both on GABAergic signaling and on progesterone receptors in the nervous system. Genetically modified mice that lack progesterone receptors do not experience myelination from progestogens. Consequently, progesterone’s effect on myelination is enhanced by estrogen, as estradiol increases progesterone receptor expression in the hypothalamus. In mice, a combination of estradiol and progesterone produced a synergistic effect on remyelination. Confirming the role of the progesterone receptor, segesterone acetate, a late-degeneration synthetic progestin highly selective for the progesterone receptor, has also been shown to improve myelin sheath formation in cerebellar slices.
Pregnenolone has also been shown to improve myelination, though it is unclear if this is due to a conversion to estrogen or progesterone. Note that not all synthetic progestins have beneficial impacts on nervous health. The synthetic progestin MPA had little effect on myelination and could even be neurotoxic.
NEUROPROTECTION OF PREGNENOLONE AND DHEA
Neuroactive steroids have profoundly neuroprotective, neurotrophic, and anti-inflammatory effects on the brain. Due to its effect on progestogens, THDOC, androstenedione, and androstanediol, finasteride administration increases hypoxic brain injury in sheep.
Pregnenolone exerts neuroprotective and neurotrophic effects. It is reduced in the striatum and cerebellum of Alzheimer’s disease patients and an inverse relationship between pregnenolone level and b amyloid synthesis, a causal molecule in the progression of Alzheimer’s disease, has been established. Pregnenolone has been shown to protect mice from b amyloid and glutamate toxicity, to stabilize microtubules, and to activate neurite outgrowth in nerve growth factor pretreated rats. As an aromatase inhibitor prevents these neuroprotective effects, pregnenolone seems to exert them through its eventual conversion into estrogen.
DHEA and DHEA sulfate have also been shown to have neuroprotective effects. Both prevent Ca+ overload in the mitochondria. During hypoxic ischemia, DHEA and DHEA sulfate have profoundly time-dependent effects. DHEA may increase neuronal damage if administered during the ischemic event, while it can provide neuroprotection if delivered hours after the event or if delivered days in advance of the event. DHEA sulfate may also protect neurons from persistent sodium currents, a result that appears to depend on s1 receptor modulation. It was also shown to be protective against neuronal death from ischemia, but only when administered 5 minutes after the event and not when administered 30 minutes after. Both DHEA and DHEA sulfate have been shown to protect against NMDA-induced excitotoxicity, though DHEA was observed to be more effective.
The protective effect of DHEA sulfate on ischemia could be blocked by using a GABAA antagonist, indicating that its protective effect may be modulated by GABAergic activity. On the other hand, DHEA’s neuroprotective effects may be dependent on its conversion into estrogen, as its protection against excitotoxicity was attenuated with the aromatase inhibitor letrozole.
NEUROPROTECTION OF PROGESTOGENS AND THDOC
Both progesterone and allopregnanolone are broadly neuroprotective and have been shown to be protective against brain injury, excitotoxicity, disease models of Alzheimer’s and Parkinson’s, and have been shown to be neurotrophic after spinal cord injury. Progesterone’s neuroprotective effect is due in part to a reduction in brain edema, mitochondrial dysfunction, lipid peroxidation, and neuronal loss.
Progestogens also reduce oxidative stress, inhibit mitochondrial permeability transition pore, regulate neuritic growth and synaptic plasticity, and promote regenerative neurogenesis. These trophic outcomes may be mediated by progestogens’ effect on neurotrophic factors like brain-derived neurotrophic factor (BDNF), which is upregulated by progesterone in the spinal cord in vivo and in cerebral cultures in vitro. Rodent studies indicate that allopregnanolone may particularly regulate adult neurogenesis, and progesterone pretreatment enhances serotonin-dependent BDNF gene expression in rats through the production of 5AR-dependent steroids. (Note that it is interesting that progesterone reduces oxidative stress. Unlike estradiol, progesterone is not able to scavenge free radicals).
The neuroprotective effects of progestogens are mediated by activity at progesterone receptors as well as the activity of allopregnanolone at the GABAA receptor, and potentially some yet undiscovered mechanisms. Studies on mirror images of steroid molecules, called ent-steroids, showed that ent-progesterone exhibited a neuroprotective effect on a mouse model of hypoxic ischemia without agonizing progesterone receptors much, while ent-allopregnanolone produced neuroprotective and antioxidant effects in a mouse model of Niemann Pick Type C disease without modulating the GABAA receptor. Nonetheless, the neurotransmitter GABA regulates adult neurogenesis, proliferating neuronal progenitors, transporting and differentiating neuroblasts, and integrating the synapses of new neurons. Allopregnanolone is being studied for the treatment of Alzheimer’s disease, as the decline in neuroactive steroids with age is a risk factor for Alzheimer’s disease progression.
Progestogens also have powerful anti-inflammatory properties in the brain. Progesterone has been shown to reduce levels of the neuroinflammatory markers IL-1b, IL-2, and IL-17, while allopregnanolone reduced expression of pro-inflammatory genes, in addition to the expression of IFN-g and IL-17 in vitro. After traumatic brain injury, treatment with progesterone reduces edema, the expression of IL-1b, TNF-a, and the accumulation of astrocytes in the cerebral cortex and hippocampus. In ischemic stroke models, progesterone reduces lesion volume and the expression of IL-1b and inducible nitric oxide synthase, while allopregnanolone reduces infarct size, reduces expression of TNF-a and IL-6, and prevents the disruption of the blood-brain barrier. Progestogens are thought to exert this anti-inflammatory effect through their modulation of GABAA receptors, as GABAA is expressed in monocytoid cells of the immune system.
As of today, there are still no studies on the neuroprotective effect of THDOC, though it is thought to produce one through similar mechanisms as allopregnanolone’s. THDOC is found in reduced levels in Alzheimer’s patients and may play a causal role in disease progression through its regulation of the enzyme acetylcholinesterase.
Progesterone is even oncoprotective in the brain, where it has been shown to produce anti-tumor benefits for brain cancers.
MOOD, ANXIETY, AND DEPRESSION
Progestogens play a crucial role in women’s mood. When progesterone and allopregnanolone peak during a female’s luteal phase of the menstrual cycle, women have increased GABAA d subunit expression, decreased g2 subunit expression, and decreased susceptibility to anxiety. Post-partum depression appears to occur because progesterone and allopregnanolone increase during pregnancy and decrease immediately after pregnancy. Interestingly, women’s birth control produces a similar result. Long-term administration of ethinyl-estradiol and levonorgestrel, two of the most common synthetic progesterones (henceforth, progestins) used for contraception, decrease cortical and hippocampal pregnenolone, progesterone, and allopregnanolone, and increased g2 GABAA subunit expression and anxious behavior in rats.
Progesterone, allopregnanolone, and THDOC exhibit anxiolytic qualities in men and women. The anxiolytic effect appears to be dependent on GABAA receptors, as the effect of allopregnanolone and progesterone can be blocked with the GABAA antagonist picrotoxin. SSRIs increase allopregnanolone in the brain in a dose-dependent fashion, likely through direct activation of the 3a-HSOR enzyme, and people who experience panic attacks exhibit reduced allopregnanolone levels. Contrarily, the sulfated versions of pregnenolone and DHEA produce an anxiogenic effect, although pregnenolone sulfate may produce a biphasic response depending on the dose.
Allopregnanolone reduces depressive behavior in animals, and diminished expression of 5AR reduces concentrations of allopregnanolone in the frontal cortex of animals. In depressed humans, plasma and CSF allopregnanolone is reduced, while THDOC levels are higher. Pregnenolone sulfate, DHEA sulfate, and DHEA can also produce an antidepressant effects in animals and humans.
Pregnenolone sulfate and DHEA sulfate have also been found to improve cognition in animal studies. In an animal model of b amyloid-induced amnesia, DHEA, DHEA sulfate, and pregnenolone sulfate attenuated amnesia in a dose-dependent manner. Interestingly, inhibition of the steroid sulfatase enzyme improved the antiamnesic effect of DHEA sulfate, indicating that preventing neuroactive steroids from being converted out of their sulfate form may improve cognition.
Nevertheless, the non-sulfated form of pregnenolone has been shown to improve cognition and function in schizophrenics. Schizophrenia is characterized by elevations in DHEA and DHEA sulfate and decreases in allopregnanolone, though it is yet unknown how pregnenolone is exerting its effect. It was observed that changes in plasma steroid levels of pregnenolone and allopregnanolone correlated with functional improvements. Interestingly, studies indicate pregnenolone produces biphasic results, where lower dosed (30 mg/day) treatments produced better outcomes than higher dosed treatments (200 mg/day).
The GABA receptors are the main target of anti-epileptic medications. Withdrawal from GABA agonists produces the delirium tremens of alcoholics and the seizures observed in benzodiazepine addicts. When progesterone and allopregnanolone peak during a female’s luteal phase of the menstrual cycle, women have increased GABAergic inhibition and decreased susceptibility to seizure.
Because pregnenolone sulfate and DHEA sulfate have opposing actions to the positive allosteric modulators of the GABAA receptor, and because of their excitatory effect at the NMDA receptor, they are pro-convulsant, while allopregnanolone is well known for its seizure prevention. Androstanediol’s positive allosteric modulation of GABAA receptors in the brain appears responsible for testosterone’s protective effect on seizure susceptibility.
ADDICTION AND SEX
Interestingly, progestogens are also involved in drug use. Post-finasteride patients have been observed to consume less alcohol. Those who consumed the most alcohol before finasteride treatment experience the greatest reductions in drinking, and this is thought to be because of finasteride’s reduction of allopregnanolone and THDOC. Ethanol acts on GABAA receptors and increases GABAergic neurotransmission, while finasteride lowers allopregnanolone and THDOC and raises isopregnanolone, reducing GABAergic potential. Both finasteride and dutasteride have been shown to attenuate the effects of alcohol.
Administration of cocaine, alcohol, nicotine, morphine, GHB, and THC increase brain and plasma levels of allopregnanolone and/or progesterone and pregnenolone in rodents. In female rodents, allopregnanolone promotes sexual behavior, while in human men, progesterone levels in the plasma correlate to the endorsement of homoerotic behavior when primed. This may potentially explain the common cultural observation of recreational drug use’s impact on sexual behavior.
In this article, we reviewed the metabolism and known cognitive and behavioral functions of the neuroactive steroids pregnenolone, pregnenolone sulfate, DHEA, DHEA sulfate, androstanediol, androsterone, progesterone, allopregnanolone, and isopregnanolone.
We learned that the effects of these molecules on cognition are mediated by their modulation of GABA, NMDA, s, serotonin type 3, nicotinic cholinergic, pregnane xenobiotic, dopamine, estrogen, and progesterone receptors, in addition to their modulation of the degradation of acetylcholine. Moreover, they exert profound trophic effects, including their integral role in the myelination of axons, and they exert neuroprotective effects against neuronal loss from traumatic, excitotoxic, hypoxic, inflammatory, and oxidant damage. These neuroactive steroids also play a crucial role in the regulation of mood, they have antidepressant and anxiolytic effects, and they improve memory and cognitive performance. Because of their actions at the GABAA receptors, some of them are anti-epileptic, while others are pro-convulsant. Finally, the progestogens are involved in the pleasure we derive from intoxicants and they modulate our sexual behavior.
In the next article, we will finally get to talking about the problem with finasteride.
Click here to read the second article in this series.
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